Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden.
Atherosclerosis. 2011 Mar;215(1):77-81. doi: 10.1016/j.atherosclerosis.2010.12.017. Epub 2010 Dec 23.
Macrophages are prominent in hypoxic areas of atherosclerotic lesions. Their secreted proteoglycans (PG) can modulate the retention of lipoproteins as well as the activity of enzymes, cytokines, and growth factors involved in atherogenesis. Versican appears to be one of the main extracellular matrix components binding LDL in the arterial intima. We have recently shown that hypoxia increases versican and perlecan expression in macrophages, and that this increase was regulated by the hypoxia inducible factor (HIF). Here we report effects of hypoxia on human monocyte-derived macrophage (HMDM) secreted glycosaminoglycans (GAG), and its interaction with LDL. After 24 h exposure to 0.5% O2 (hypoxia), metabolically labeled GAG of secreted PG had higher affinity for LDL compared to 21% O2 (control cells). GAG secreted by HMDM in hypoxia were found to be more sulfated and longer which might be responsible for the increased affinity of LDL for these GAG chains. These results indicate that hypoxia induced changes in macrophage GAG biosynthesis have important consequences for the interaction with LDL. If present in vivo, an augmented association of GAG with LDL might contribute to the development of atherosclerosis in hypoxic intima.
巨噬细胞在动脉粥样硬化病变的缺氧区域中非常显著。它们分泌的蛋白聚糖（PG）可以调节脂蛋白的保留以及参与动脉粥样硬化形成的酶、细胞因子和生长因子的活性。神经节苷脂似乎是结合在动脉内膜中 LDL 的主要细胞外基质成分之一。我们最近表明，缺氧会增加巨噬细胞中 versican 和 perlecan 的表达，并且这种增加受到缺氧诱导因子（HIF）的调节。在这里，我们报告了缺氧对人单核细胞衍生的巨噬细胞（HMDM）分泌糖胺聚糖（GAG）的影响，以及其与 LDL 的相互作用。在 0.5% O2（缺氧）下暴露 24 小时后，与 21% O2（对照细胞）相比，分泌 PG 的代谢标记 GAG 对 LDL 具有更高的亲和力。发现在缺氧条件下由 HMDM 分泌的 GAG 具有更高的硫酸化程度和更长的链长，这可能是导致这些 GAG 链与 LDL 亲和力增加的原因。这些结果表明，巨噬细胞 GAG 生物合成的缺氧诱导变化对与 LDL 的相互作用具有重要影响。如果在体内存在，GAG 与 LDL 的关联增强可能会导致缺氧内膜中动脉粥样硬化的发展。
